Thyroid cancer is the fastest growing cancer diagnosis in the U.S. with approximately 30,000 new cases of thyroid cancer occurring each year. Thyroid cancer occurs three-times more often in women than in men and is most common after age 30, although it can occur in any age group. Its aggressiveness increases significantly in older patients. Since the advent of high-resolution ultra-sonography and other sensitive imaging techniques, the number of patients with thyroid nodules requiring clinical evaluation has increased dramatically and approaches 50% of the U.S. population.
Fine needle aspiration (FNA) biopsy has reduced the number of diagnostic thyroidectomies for benign thyroid neoplasms, (Greaves et al,. Cancer. 90(6):335-341 (2000); Baloch, Z. W. et al., Diagn Cytopathol. 26(1):41-44 (2002); Gharib, H. et al., Ann Intern Med. 118(4):282-289 (1993); Cersosimo, E. et al., Mayo Clin Proc. 68(4):343-348 (1993); Gharib, H. et al., Clin Lab Med. 13(3):699-709 (1993); Hooft, L. et al., Thyroid. 14(4):287-293 (2004)) but may be nondiagnostic or show indeterminate or suspicious cytologic features in 20% to 30% of all thyroid nodules (Greaves et al. Cancer. 90(6):335-341 (2000); Baloch, Z. W. et al., Diagn Cytopathol. 26(1):41-44 (2002); Gharib, H. et al., Ann Intern Med. 118(4):282-289 (1993)). Because the risk of malignancy is anywhere from 5% to 30% for follicular tumors and about 50% in nodules suspicious for papillary thyroid cancer, diagnostic thyroidectomy is usually recommended. Unfortunately, no preoperative clinical or imaging factors can reliably determine which patients with suspicious, nondiagnostic or indeterminate FNA cytologic findings should undergo thyroidectomy (Tuttle, R. M. et al., Thyroid. 8(5):377-383 (1998); Basu, D. et al., Diagn Cytopathol. 8(1):23-27 (1992); Eldar, S. et al., Histopathology. 34(5):453-461 (1999); Tyler, D. S. et al., Surgery. 116(6):1054-1060 (1994)).
Many prognostic scoring systems (TNM, AMES, AGES, MACIS, EORTC) have been used to estimate disease-free survival and cause-specific mortality in patients with thyroid cancer (Kebebew, E. et al., World J Surg. 24(8):942-951 (2000); Brierley, J. D. et al., Cancer. 79(12):2414-2423 (1997); Sanders, L. E. et al., Arch Surg. 133(4):419-425 (1998); Dean, D. S. et al., Cancer Control. 7(3):229-239 (2000)). The main use of these risk classification systems is to identify patients with a poor prognosis, to ensure that they receive additional treatment such as radioiodine ablation, and get closer follow-up monitoring (Mazzaferri, E. L. et al., J Clin Endocrinol Metab. 88(4):1433-1441 (2003)). Unfortunately, none of these staging systems include data that are completely available preoperatively to guide the extent of initial surgical resection necessary (Kebebew, E. et al., World J Surg. 24(8):942-951 (2000)). Therefore, preoperative molecular markers that could reliably stratify low-risk vs. high-risk patients would be useful in the initial surgical decision-making regarding the extent of thyroidectomy and the need for lymph node dissection.
We have used cDNA array analysis to identify candidate diagnostic and extent of disease markers in thyroid neoplasms that would be intermediate or suspicious on FNA cytology (Kebebew, E. et al., Ann Surg. 242(3):353-361; discussion 361-353 (2005); Kebebew, E. et al., Surgery in press (2005)). We found 6 novel candidate diagnostic and extent of disease markers of malignant thyroid neoplasms that were confirmed by reverse-transcriptase-polymerase-chain-reaction (RT-PCR); ECM1 (U68186, UniGene ID Hs.81071), TMPRSS4 (AF179224, UniGene ID Hs.161985), ANGPT2 (AF004327, UniGene ID Hs.583870), TIMP1 (NM—003254, UniGene ID Hs.522632), EFNB2 (L38734, UniGene ID Hs.149239) and EGFR (NM—005228, UniGene ID Hs.488293). In this study, we determine the diagnostic accuracy and the ability to predict disease aggressiveness using a multigene RT-PCR assay of these 6 novel candidate markers in combination.